Project Summary/Abstract Nitrogen and oxygen heterocycles are ubiquitous components of pharmaceutical drugs essential for human health. A particularly attractive approach to nitrogen containing compounds is the modification of cheap and readily available amines via C?H bond functionalization. However, methods that efficiently accomplish this task typically require the use of expensive transition metal catalysts and/or oxidants. This proposal is focused on the design and development of efficient and practical methods for amine functionalization. The main goal is the alpha-functionalization of amines through conceptually new and underdeveloped methods of substrate activation. One tactic will achieve amine C?H bond functionalization in redox-neutral fashion by combining a reductive amine N-alkylation with an oxidative alpha-functionalization, utilizing azomethine ylides as reactive intermediates. Water is generated as the only byproduct and the only required promoters are cheap carboxylic acids. A second strategy facilitates the functionalization of cyclic amines via a novel method involving intermolecular hydride transfer. This approach does not require protecting groups and provides valuable secondary amine products. Reactions are highly enantiospecific and enable late-stage functionalization of drug candidates. A third goal is the stereoselective synthesis of chiral oxygen heterocycles via oxocarbenium ions. These highly reactive intermediates have been notoriously difficult to control in enantioselective settings, in part because their direct formation from aldehydes and alcohols generally requires highly acidic conditions. A novel dual catalysis strategy enables the generation of oxocarbenium ions under unusually mild conditions, facilitating previously unknown enantioselective processes. In addition to targeting the rapid preparation of compounds related to structures with known biological activities, efforts will center on the development of particularly powerful reactions that rapidly produce new polycyclic amines and ethers. A priority is the generation of new structural frameworks that are absent from current drug discovery screening libraries.